Abstract：
OBJECTIVE: Inflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI.
METHODS: Rats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro.
RESULTS: In vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-β. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1β). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1β expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages.
CONCLUSIONS: Gabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.
METHODS: Rats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro.
RESULTS: In vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-β. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1β). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1β expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages.
CONCLUSIONS: Gabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.
摘要：
目的：炎症调节心肌梗死（MI）后的心室重构，和加巴喷丁发挥抗炎作用。我们研究了MI后加巴喷丁的抗炎作用和机制。
方法:大鼠分为假手术组(n=12),MI组（n=20），MI+加巴喷丁组(n=16)。左冠状动脉结扎诱发MI。在体外检查加巴喷丁对THP-1来源的巨噬细胞的作用。
结果：体内，MI后1周，加巴喷丁显著降低诱导型一氧化氮合酶（iNOS；M1巨噬细胞标记）的表达和降低促炎因子（肿瘤坏死因子[TNF]-α和白细胞介素[IL]-1β）。加巴喷丁上调M2巨噬细胞标志物精氨酸酶-1，以及CD163的表达，并增加抗炎因子的表达，包括几丁质酶样3，IL-10和转化生长因子-β。心肌梗死四周后，心功能,梗死面积,加巴喷丁治疗后心脏纤维化改善。加巴喷丁抑制大鼠心梗后交感神经活动并减少心室电不稳定性。加巴喷丁治疗后，酪氨酸羟化酶和生长相关蛋白43被抑制。加巴喷丁下调神经生长因子（NGF）和减少的促炎因子（iNOS，TNF-α,和IL-1β）。体外，加巴喷丁减少NGF，iNOS,TNF-α,和IL-1β在脂多糖刺激的巨噬细胞中的表达。机制研究表明，过氧化物酶体增殖物激活受体γ拮抗剂GW9662减弱了加巴喷丁的作用。此外，加巴喷丁降低了巨噬细胞质膜中α2δ1的表达，并降低了巨噬细胞的钙含量。
结论：加巴喷丁通过过氧化物酶体增殖物激活受体-γ激活抑制炎症反应和防止钙超载，从而减轻心脏重构。
方法:大鼠分为假手术组(n=12),MI组（n=20），MI+加巴喷丁组(n=16)。左冠状动脉结扎诱发MI。在体外检查加巴喷丁对THP-1来源的巨噬细胞的作用。
结果：体内，MI后1周，加巴喷丁显著降低诱导型一氧化氮合酶（iNOS；M1巨噬细胞标记）的表达和降低促炎因子（肿瘤坏死因子[TNF]-α和白细胞介素[IL]-1β）。加巴喷丁上调M2巨噬细胞标志物精氨酸酶-1，以及CD163的表达，并增加抗炎因子的表达，包括几丁质酶样3，IL-10和转化生长因子-β。心肌梗死四周后，心功能,梗死面积,加巴喷丁治疗后心脏纤维化改善。加巴喷丁抑制大鼠心梗后交感神经活动并减少心室电不稳定性。加巴喷丁治疗后，酪氨酸羟化酶和生长相关蛋白43被抑制。加巴喷丁下调神经生长因子（NGF）和减少的促炎因子（iNOS，TNF-α,和IL-1β）。体外，加巴喷丁减少NGF，iNOS,TNF-α,和IL-1β在脂多糖刺激的巨噬细胞中的表达。机制研究表明，过氧化物酶体增殖物激活受体γ拮抗剂GW9662减弱了加巴喷丁的作用。此外，加巴喷丁降低了巨噬细胞质膜中α2δ1的表达，并降低了巨噬细胞的钙含量。
结论：加巴喷丁通过过氧化物酶体增殖物激活受体-γ激活抑制炎症反应和防止钙超载，从而减轻心脏重构。
